Psychitric Update: St. John’s Wort as an Antidepressant

During the past year, the use of extracts of Hypericum perforatum (St. John’s wort) for the treatment of clinical depression has attracted considerable attention in the popular press. Increasingly, physicians are being asked by their patients about this herbal medication: What is it? Does it really work? Is it safe? The inaugural issue of the McLean Hospital Psychiatric Update is devoted to answering these questions. Future issues will address other topics of concern to busy clinicians. We welcome suggestions from our readers for future topics.

Extracts of the plant Hypericum perforatum, a member of the Hypericaceae family, have been used in folk medicine for a variety of indications, including wound healing, kidney and lung ailments, insomnia and depression. Its medicinal use was first recognized by the ancient Greeks. Extracts of St. John's wort are licensed in Germany for the treatment of anxiety, depression and sleep disorders. Nearly three million prescriptions for St. John’s wort were written in Germany in 1993 alone. In the United States, where preparations of St. John’s wort are sold in health food stores and pharmacies without a prescription, accurate estimates of its use are not possible. Based on sales alone, however, well over a million Americans may be taking this phytomedicine.

Evidence of Efficacy: Extracts of hypericum are more efficacious than placebo in treating mild to moderately severe depressive disorders. At least 23 randomized trials with more than 1,750 outpatients support this conclusion. Fifteen studies were placebo controlled and eight compared hypericum with other drug treatments. In 13 trials comparing a single hypericum preparation with placebo, 22.3% responded to placebo versus 55.1% in the hypericum groups. In trials comparing single preparations of hypericum with standard antidepressants, 63.9% of the patients receiving hypericum responded versus 58.5% of those taking standard antidepressants.

Evidence of Tolerability: In placebo-controlled trials, only 0.4% of hypericum patients dropped out because of side effects versus 1.6% of placebo patients. A total of 4.1% of hypericum patients reported side effects compared with 4.8% of patients on placebo. In trials of hypericum against other antidepressants, hypericum was better tolerated (4.0% of hypericum patients dropped out versus 7.7% for standard antidepressants). Comparison drugs were limited to older cyclic antidepressants (maprotiline, imipramine and amitriptyline) with moderate to high sedative and anticholinergic side effects. Direct comparisons with newer, better tolerated antidepressants remain to be done.

Mechanism of Action: The mechanism of the antidepressant action of St. John’s wort is not known. Commercially available preparations contain at least 10 constituents that may contribute to a therapeutic action. These include naphthodianthrons, flavonoids and bioflavonoids. An early study suggested hypericum may inhibit the enzyme monoamine oxidase (MAO). Later investigations have failed to confirm significant MAO inhibition and it is unlikely that MAO inhibition contributes to the clinical effects of St. John’s wort. Recent studies in vitro demonstrate inhibition of serotonin reuptake by hypericum. One study suggests an inhibiting effect on norepinephrine reuptake. Hypericum also inhibits the enzyme dopamine-b-hydroxylase in vitro. A novel proposal is that hypericum reduces cytokine expression (interleukin-6); interleukins have been hypothesized to provoke depression in susceptible individuals.

Dosage Recommendations: Considerable confusion exists about the optimal dosage of St. John’s wort. Typically, dosing recommendations are based on milligrams of total hypericin extracts. This is somewhat problematic in that constituents other than hypericum may contribute to the therapeutic effects of St. John’s wort. Most studies have used 0.75 mg to 2.7 mg of total hypericin daily, which corresponds to a dose of 500 mg to 900 mg daily of commercially available preparations of St. John’s wort. In this country, the most commonly available preparation is a 300 mg tablet or capsule, which is usually administered three times a day. As with other antidepressants, a trial of St. John’s wort should last at least six weeks.

Future Studies: Two major studies slated to begin this fall should answer remaining questions about the efficacy, safety and tolerabilty of St. John’s wort. McLean’s Depression & Anxiety Disorders Outpatient Service will conduct a double-blind, placebo-controlled trial of AlterraTM (hypericum perforatum), a new extended-release form of St. John’s wort, in 80 depressed outpatients. In another significant study, the National Institute of Mental Health is sponsoring a three-year, $4.3 million trial comparing St. John’s wort with ZoloftR (sertraline hydrochloride) and placebo. This study will enroll 336 patients at several sites across the country, including McLean Hospital. Individuals interested in participating in either of these studies should contact McLean researchers in the fall of 1998 (1-800-333-0338).

Summary: Based on currently available evidence, St. John’s wort is probably effective in treating outpatients with mild to moderate depression. Its efficacy in treating severely depressed inpatients and its safety for long-term administration have not been systematically evaluated. St. John’s wort appears to be better tolerated than older cyclic antidepressants and may be useful in patients who are unable to take synthetic antidepressants. No controlled studies support combining St. John’s wort with prescription antidepressants and the safety of such combinations has not been evaluated.

Until more definitive data are available, we offer the following guidelines to clinicians: 1) All patients taking St. John’s wort should be followed by a physician who is familiar with this phytomedicine. 2) St. John's wort cannot yet be considered a first-line agent and its use is most appropriately reserved for mildly to moderately depressed outpatients who are intolerant of newer synthetic antidepressants. 3) Although St. John’s wort appears to be well tolerated and safe, physicians should be alert to the possibility of unreported drug interactions and adverse effects, including adverse effects that may emerge with chronic administration.

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largest psychiatric teaching affiliate of Harvard Medical School, an affiliate of
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